Vascular disorders underpin the biggest killers in the Western world, including heart attack and stroke. Thus, an improved understanding of endothelial cell response to stress and damage—the first step towards atherosclerosis—would be of major medical importance. Now, Briot et al. describe new data showing that down-regulation of Notch1 protein expression accompanies endothelial cell (EC) activation and mediates pathological changes in this cell type.

Notch proteins are transmembrane receptors that drive signaling pathways known to be involved in vascular development and remodeling. Recent GWAS studies highlighted Notch pathway genes in coronary artery disease; however, the protein’s function in adult endothelial homeostasis was unexplored. The authors show that Notch1—the main family member expressed by ECs—is down-regulated in aortic ECs in response to a high-fat diet in mice, or exposure to proatherogenic oxidized lipids and inflammatory mediators tumor necrosis factor–α and interleukin-1β (IL-1β). Moreover, much of the cellular response to the oxidized lipids could be attributed to Notch repression. Human aortic endothelial cells in vitro and in vivo mouse models demonstrated that decreased Notch signaling promoted inflammatory cell binding to ECs and increased expression of key players in disease, including proinflammatory IL-8 and CXCL1. Notch actively antagonized an inflammatory phenotype in ECs when the protein was artificially overexpressed in cells faced with stressors that typically result in Notch repression. Last, the implications of Notch down-regulation in ECs became very clear when cell-specific hemizygous knock-out mice combined with an atherosclerosis model displayed accelerated disease. It seems fortunate that ECs could restore normal Notch expression when the high-fat diet was stopped, but if and when this feature of EC activation becomes permanent is not yet known.

The new work highlights restoration of the Notch signaling pathway as a potential strategy to prevent atherosclerosis. Although the authors show some ways to manipulate this response (for example, Stat3 inhibition), the importance of EC activation in acute infection and wound repair means that manipulating this pathway will require careful management, and likely an EC-specific strategy would be needed to preserve desirable Notch functions in inflammatory cells.